The G Protein-Coupled Receptor 15 (GPR15), also called BOB (Brother Of Bonzo), belongs to the superfamily of Rhodopsin-like 7TM receptors (seven transmembrane domain receptors) also known as G-protein coupled receptors (GPCRs). GPR15 is an orphan G protein coupled receptor for which no ligand is known. GPR15 was cloned in 1995 using degenerate oligonucleotide primers based on highly conserved regions in TM3 of the opioid-like genes GPR7 and GPR8 (Heiber, M., et al. (1996) Genomics 32, 462-65).
The GPR15 gene is localized to chromosome 3q11.2-q13.1, and its closest homolog is the orphan GPR25, with 32% identity. Other receptors like the Apelin and the Angiotensin receptors share roughly 30% homology with GPR15 (Fredricksson, et al. (2003) Molecular Pharmacology, Vol. 63(6), 1256-72). GPR15 is also homologous to the interleukin 8b receptor and to chemokine receptors; although the protein lacks several hallmarks of chemokine receptors, it shares an amino-terminal motif rich in tyrosine residues with at least with CCR5 (Farzan, et al. (1997) Journal of Experimental Medicine, Vol. 186(3): 405-11).
The GPR15 ligand and receptor system (“GPR15 L/R system”) is involved in maintaining intestinal epithelium homeostasis. GPR15 expression was detected in the GI tract in the mucosa of the gut as well as in the HT29 cell line (Clayton, et al. (2001) Am J Pathol, 159(5), 1933-9) and on lymphocytes (see, e.g., PCT publication W02005/040823, assigned to Bayer Healthcare AG).
GPR15 is expressed in human CD4(+) T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells, and in regulatory T cells (Tregs). Recently GPR15 was claimed as involved in Treg homing toward the lamina propria of the large intestine, a tissue where we know the GPR15 ligand (“GPR15L”) is highly expressed (Kim, et al. (2013) Science. June 21; 340(6139)).
The GPR15 L/R system has been implicated in a variety of pathologic conditions in the literature. By way of non-limiting examples:
(1) Lack of GPR15 results in severe body weight loss with increased inflammation and tissue damage in the Citrobacterrodentium infection-induced Inflammatory Bowel Disease (IBD) mouse model (Kim et al. (2013) Science 340(6139):1456-9).
(2) GPR15L is up-regulated in human skin transplantation and mouse skin wound healing models suggesting a role of GPR15L/R system in reducing inflammation or triggering (re-)epithelialization mechanisms. In addition, GPR15L is strongly expressed in skin lesions of psoriatic patients (Gudjonsson et al. (2009) Journal of Investigative Dermatology Vol. 129(12): 2795-2804). Treatment by AIN-457 decreases GPR15L expression in correlation with amelioration of the PASI (Hueber, et al. (2010) Sci Transl Med. Vol. 2(52), 52ra72).
(3) GPR15 locus methylation is significantly associated with smoking behaviour (Sun, et al. (2013) Hum Genet, Vol. 132(6), 1027-1037)(Wan, et al. (2012) Hum Mol Genet Vol. 21(13), 3073-82); and the rs1675521 A allele is associated with an increased asthma exacerbation (p=0.007) (Sharma, et al. (2011) Congress ATS 2011 Abstract 19595). GPR15L methylation and expression in the oral mucosa is significantly associated with smoking behavior (Boyle J O, et al. Cancer Pre Res Vol. 3(3), 266-78). These data suggest a role of the GPR15L/R system in the maintenance of the lung epithelium homeostasis in a disease context.
In addition, GPR15 is differentially expressed in rheumatoid arthritis (RA) and non-RA synovial tissue. RNA was present in RA monocytes/macrophages, and protein was expressed by monocytes/macrophages and neutrophils in which levels were higher in RA than in normal peripheral blood (Cartwright, et al. (2010) Rheumatology, 49: i43-i45).
GPR15 is, among other GPCRs such as CCR5, CXCR4, CCR3, CCR2b, CCRB, CXCR6, GPR1, CX3CR1, a co-receptor utilized by HIV and related viruses to infect target cells. In this context, GPR15 has been implicated as mediating gp120-induced calcium signalling and microtubule loss in HT-29 cells (a human colon colorectal adenocarcinoma cell line). These calcium and microtubule changes were previously shown to induce enteropathy-like malabsorption and increased paracellular permeability associated with HIV infection; it has therefore been postulated that gp120-induced GPR15 activation causes HIV enteropathy (Clayton, et al. (2001) Am J Pathol, 159(5), 1933-9).
External publications describe the relationship between Epstein-Barr Virus infection and consequent GPR15 expression and/or promoter methylation (Caliskan, et al. (2011) Hum Mol Genet, Vol. 20(8), 1643-52; Hernando, et al. (2013) Genome Biol Vol. 14(1):R3; Matsusaka, et al. (2011) Cancer Res Vol. 71(23):7187-97.